1. Field of Invention
The field of the currently claimed embodiments of this invention relates to systems and methods of predicting risk of ventricular arrhythmias.
2. Discussion of Related Art
Sudden cardiac death (SCD) is a major health problem in the industrialized world. SCD often occurs in healthy individuals without prior history of heart disease. The early diagnosis of arrhythmia has the potential to significantly reduce mortality due to SCD. Clinical studies have demonstrated that instability in the QT interval of the electrocardiogram (ECG), which is the global manifestation of instability in ventricular repolarization, predicts propensity to arrhythmias. However, a robust methodology to assess QT interval instability and thus predict propensity to arrhythmia in a patient-specific manner is currently lacking.
Clinical studies have demonstrated that the QT interval instability in the ECG signal is associated with a propensity for lethal arrhythmias. A methodology that allows the physician to predict the development of instabilities in the QT interval in a patient-specific manner, and thus predict the patient's propensity for arrhythmias, would be a significant step forward in improving SCD risk stratification and in preventing loss of human life.
ECG (or electrogram if recorded from an implanted cardioverter-defibrillator (ICD) device) is the most widely-used tool in the diagnosis of heart rhythm disorders. The QT interval of the ECG (interval between Q and T deflections, FIG. 1A) has been found to be unstable in the diseased heart (FIG. 1B). QT interval instability has been reported in long QT syndrome patients (Merri M, Moss A J, Benhorin J, Locati E H, Alberti M, Badilini F. Relation between ventricular repolarization duration and cardiac cycle length during 24-hour Holter recordings. Findings in normal patients and patients with long QT syndrome. Circulation. 1992; 85(5):1816-1821; Yamauchi S, Yamaki M, Watanabe T, Yuuki K, Kubota I, Tomoike H. Restitution properties and occurrence of ventricular arrhythmia in LQT2 type of long QT syndrome. J Cardiovasc Electrophysiol. 2002; 13(9):910-914; Chinushi M, Restivo M, Caref E B, El-Sherif N. Electrophysiological basis of arrhythmogenicity of QT/T alternans in the long-QT syndrome: tridimensional analysis of the kinetics of cardiac repolarization. Circ Res. 1998; 83(6):614-628). QT prolongation and abnormal QT dynamics have been found in acute myocardial infarction patients (Chevalier P, Burri H, Adeleine P, Kirkorian G, Lopez M, Leizorovicz A, Andre-Fouet X, Chapon P, Rubel P, Touboul P. QT dynamicity and sudden death after myocardial infarction: results of a long-term follow-up study. J Cardiovasc Electrophysiol. 2003; 14(3):227-233; Schwartz P J, Wolf S. QT interval prolongation as predictor of sudden death in patients with myocardial infarction. Circulation. 1978; 57(6):1074-1077; Bonnemeier H, Wiegand U K, Bode F, Hartmann F, Kurowski V, Katus H A, Richardt G. Impact of infarct-related artery flow on QT dynamicity in patients undergoing direct percutaneous coronary intervention for acute myocardial infarction. Circulation. 2003; 108(24):2979-2986; Szydlo K, Trusz-Gluza M, Wita K, Filipecki A, Orszulak W, Urbanczyk D, Krauze J, Kolasa J, Tabor Z. QT/RR relationship in patients after remote anterior myocardial infarction with left ventricular dysfunction and different types of ventricular arrhythmias. Ann Noninvasive Electrocardiol. 2008; 13(1):61-66). Berger et al. reported an increased QT interval variability in dilated cardiomyopathy patients (FIG. 1B) (Berger R D, Kasper E K, Baughman K L, Marban E, Calkins H, Tomaselli G F. Beat-to-beat QT interval variability: novel evidence for repolarization lability in ischemic and nonischemic dilated cardiomyopathy. Circulation. 1997; 96(5):1557-1565). These studies indicate that the instability in the QT interval is an important indicator of cardiac rhythm disorder.
Instability in the QT interval is a manifestation of instability in repolarization in the heart. At the cellular level, instability in myocyte repolarization is assessed from the dynamics of its action potential duration (APD). APD instability and its implication for arrhythmogenesis have been extensively studied (Laurita K R, Girouard S D, Rosenbaum D S. Modulation of ventricular repolarization by a premature stimulus. Role of epicardial dispersion of repolarization kinetics demonstrated by optical mapping of the intact guinea pig heart. Circ Res. 1996; 79(3):493-503; Akar F G, Rosenbaum D S. Transmural electrophysiological heterogeneities underlying arrhythmogenesis in heart failure. Circ Res. 2003; 93(7):638-645; Sampson K J, Henriquez C S. Simulation and prediction of functional block in the presence of structural and ionic heterogeneity. Am J Physiol 2001; 281(6):H2597-2603; Chen X, Fenton F H, Gray R A. Head-tail interactions in numerical simulations of reentry in a ring of cardiac tissue. Heart Rhythm. 2005; 2(9):1038-1046; Weiss J N, Chen P S, Qu Z, Karagueuzian H S, Lin S F, Garfinkel A. Electrical restitution and cardiac fibrillation. J Cardiovasc Electrophysiol. 2002; 13(3):292-295; Gilmour R F, Chialvo D R. Electrical Restitution, Critical Mass, and the Riddle of Fibrillation. J. Cardiovasc Electrophysiol. 1999; 10(8):1087-1089; Banville I, Gray R A. Effect of action potential duration and conduction velocity restitution and their spatial dispersion on alternans and the stability of arrhythmias. J Cardiovasc Electrophysiol. 2002; 13(11):1141-1149; Elharrar V, Surawicz B. Cycle length effect on restitution of action potential duration in dog cardiac fibers. Am J. Physiol. 1983; 244(6):H782-792; Gilmour R F, Otani N F, Watanabe M A. Memory and complex dynamics in cardiac Purkinje fibers. Am J. Physiol. 1997; 272(4):H1826; Franz M R, Swerdlow C D, Liem L B, Schaefer J. Cycle length dependence of human action potential duration in vivo. Effects of single extrastimuli, sudden sustained rate acceleration and deceleration, and different steady-state frequencies. J Clin Invest. 1988; 82(3):972-979). It is thus reasonable to expect that concepts developed to determine instability in APD could be translated to the clinic and applied in the evaluation of the patient's QT interval instability. The efforts to assess instability in APD are therefore reviewed below.
APD depends on the preceding diastolic interval (DI). This relationship is termed APD restitution. A standard APD restitution curve is constructed by delivering S2 pacing stimuli following the same S1 pacing train for a broad range of S1-S2 intervals; S1 pacing is at a constant rate. In a dynamic APD restitution protocol, tissue is paced continuously at different rates; the last beat for each pacing episode is used to construct the APD restitution. The restitution hypothesis postulates that APD can be predicted from the preceding DI and the restitution relationship (FIG. 2), and implicates the maximum slope of the APD restitution curve as the sole predictor of repolarization instability and thus of propensity to arrhythmia (Nolasco J B, Dahlen R W. A graphic method for the study of alternation in cardiac action potentials. J Appl Physiol. 1968; 25(2):191-196; Garfinkel A, Kim Y H, Voroshilovsky O, Qu Z, Kil. Preventing ventricular fibrillation by flattening cardiac restitution. PNAS. 2000; 97(11); Riccio M L, Koller M L, Gilmour R F. Electrical restitution and spatiotemporal organization during ventricular fibrillation. Circ Res. 1999; 84:955-963). Indeed, studies have shown that steep restitution increases the functional heterogeneity of repolarization (Garfinkel A, Kim Y H, Voroshilovsky O, Qu Z, Kil. Preventing ventricular fibrillation by flattening cardiac restitution, PNAS, 2000; 97(11); Riccio M L, Koller M L, Gilmour R F. Electrical restitution and spatiotemporal organization during ventricular fibrillation. Circ Res, 1999; 84(955-963); Qu Z, Garfinkel A, Chen P S, Weiss J N. Mechanisms of discordant alternans and induction of reentry in simulated cardiac tissue. Circulation. 2000; 102(14):1664-1670; Cao J M, Qu Z, Kim Y H, Wu T J, Garfinkel A, Weiss J N, Karagueuzian H S, Chen P S. Spatiotemporal heterogeneity in the induction of ventricular fibrillation by rapid pacing: importance of cardiac restitution properties. Circ Res. 1999; 84(11):1318-1331), and leads to arrhythmogenesis (Akar F G, Rosenbaum D S. Transmural electrophysiological heterogeneities underlying arrhythmogenesis in heart failure. Circ Res. 2003; 93(7):638-645; Chen X, Fenton F H, Gray R A. Head-tail interactions in numerical simulations of reentry in a ring of cardiac tissue. Heart Rhythm 2005; 2(9):1038-1046). Studies have also reported that a steep restitution causes APD alternans at the cellular level (Nolasco J B, Dahlen R W. A graphic method for the study of alternation in cardiac action potentials. J Applied Physiol. 1968; 25(2):191-196) and results in spiral wave breakup and the induction of ventricular fibrillation (VF) (Weiss J N, Chen P S, Qu Z, Karagueuzian H S, Lin S F, Garfinkel A. Electrical restitution and cardiac fibrillation. J Cardiovasc Electrophysiol. 2002; 13(3):292-295; Gilmour R F, Chialvo DR. Electrical Restitution, Critical Mass, and the Riddle of Fibrillation. J. Cardiovasc Electrophysiol. 1999; 10(8):1087-1089).
The assessment of APD stability, and thus the prediction of propensity to arrhythmia based on the criterion of maximum restitution slope >1 is, however, not always accurate: arrhythmia has been induced with slope <1, and failed to be induced with slope >1 (Elharrar V, Surawicz B. Cycle length effect on restitution of action potential duration in dog cardiac fibers. Am J. Physiol. 1983; 244(6):H782-792; Gilmour R F, Otani N F, Watanabe M A. Memory and complex dynamics in cardiac Purkinje fibers. Am J. Physiol. 1997; 272(4):H1826; Franz M R, Swerdlow C D, Liem L B, Schaefer J. Cycle length dependence of human action potential duration in vivo. Effects of single extrastimuli, sudden sustained rate acceleration and deceleration, and different steady-state frequencies. J Clin Invest. 1988; 82(3):972-979; Saitoh H, Bailey J C, Surawicz B. Action potential duration alternans in dog Purkinje and ventricular muscle fibers. Further evidence in support of two different mechanisms. Circulation. 1989; 80(5):1421-1431; Karagueuzian H S, Khan S S, Hong K, Kobayashi Y, Denton T, Mandel W J, Diamond G A. Action potential alternans and irregular dynamics in quinidine-intoxicated ventricular muscle cells. Implications for ventricular proarrhythmia. Circulation. 1993; 87(5):1661-1672). Huang et al., evaluating the effect of previous activations on APD with a statistical approach (Huang J, Zhou X, Smith W M, Ideker R E. Restitution properties during ventricular fibrillation in the in situ swine heart. Circulation. 2004; 110(20):3161-3167), reported that during VF, the contribution of preceding APD to current APD is as significant as the contribution of the preceding DI. These results indicate that events that precede DI also affect stability of APD.
The events that precede DI represent the activation history, i.e. memory (FIG. 3). Memory has been found to affect APD and its restitution. Elharrar et al (Elharrar V, Surawicz B. Cycle length effect on restitution of action potential duration in dog cardiac fibers. Am J. Physiol. 1983; 244(6):H782-792) reported that APD restitution depended on pacing rate. Gilmour and Otani (Otani N F, Gilmour R F. Memory Models for the Electrical Properties of Local Cardiac Systems. J. Theor. Biol. 1997; 187:409-436) found that that memory can enhance or diminish APD stability. These studies indicate that both restitution and memory govern APD stability.
Similar to instability in APD, the restitution concept has been used to evaluate QT interval instability in the clinic by evaluating the slope of the dependence of the QT interval on the preceding TQ interval or preceding RR interval (since QT interval+QT interval is equal to RR interval) (FIG. 1A). The latter relationship has been tested as an arrhythmia risk predictor (Yamauchi S, Yamaki M, Watanabe T, Yuuki K, Kubota I, Tomoike H. Restitution properties and occurrence of ventricular arrhythmia in LQT2 type of long QT syndrome. J Cardiovasc Electrophysiol. 2002; 13(9):910-914; Fossa A A, Wisialowski T, Crimin K, Wolfgang E, Couderc J-P, Hinterseer M, Kaab S, Zareba W, Badilini F, Sarapa N. Analyses of Dynamic Beat-to-Beat QT-TQ Interval (ECG Restitution) Changes in Humans under Normal Sinus Rhythm and Prior to an Event of Torsades de Pointes during QT Prolongation Caused by Sotalol. Ann Noninvasive Electrocardiol. 2007; 12(4):338-348; Gilmour R F, Riccio M L, Locati E H, Maison-Blanche P, Coumel P, Schwartz P J. Time- and rate-dependent alterations of the QT interval precede the onset of torsade de pointes in patients with acquired QT prolongation. J Am Coll Cardiol. 1997; 30:209-217). However, such an approach is invasive and requires constant pacing, thus eliminating the role of memory (i.e. the dependence of a QT interval on preceding TQ and QT intervals). It is therefore clear that a robust methodology, which can detect instability of the QT interval directly from the clinical ECG and without invasive pacing is currently lacking. If such a methodology is developed, it could be used to predict an impending arrhythmia event from a patient clinical ECG or from an ICD electrogram recording.